Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In response to humoral and mechanical stimuli, the myocardium adapts to increased work load through hypertrophy of individual muscle cells. Myocardial hypertrophy is characterized by an increase in cell size in the absence of cell division and is accompanied by changes in gene expression. Angiotensin II (Ang II), the effector peptide of the renin-angiotensin system (RAS), regulates volume and electrolyte homeostasis and is involved in cardiac and vascular growth in rats. In this review, the role of RAS in myocyte protein synthesis (myocyte hypertrophy) and in induction of gene expression will be discussed in rat cardiomyocytes in culture. Traditional RAS can be considered as a system in which circulating Ang II is delivered to target tissues or cells. However, a local RAS has also been described in cardiac cells and evidence has been accumulated for autocrine and/or paracrine pathways by which biological actions of Ang II can be mediated. These actions of Ang II are primarily mediated through Ang II receptors subtype I (AT1-R). When evaluating the effects of Ang II in situ, both changes in circulating levels and local production have to be taken into account. Contrasting results have been found concerning the in vitro effect of Ang II on the protein synthesis in cardiac myocytes and can be at least partly be attributed to methodological problems such as assay of de novo protein synthesis and isolation and separation procedure of cardiac myocytes. The Ang II-induced hypertrophic effect also depends on the existence of nonmyocytes in a cardiocyte culture. In rat cardiocytes, AngII also causes induction of many immediately-early genes (c-fos, c-jun, jun-B, Egr-1 and c-myc) and induces also late markers of cardiac hypertrophy (skeletal alpha-actin and atrial natriuretic peptide expression) and growth factors (TGF-beta 1 gene expression). In vivo AngII via AT1-R, causes not only ventricular hypertrophy but also a shift to the fetal phenotype of the myocardium. Angiotensin-converting enzyme inhibitors and AngII receptor antagonists of the subtype I not only induce the regression but also prevent the development of cardiac hypertrophy in experimental rat models.
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PMID:Antagonism of the renin-angiotensin system, hypertrophy and gene expression in cardiac myocytes. 1042 Mar 93

It has been proposed that the local renin-angiotensin system is activated in the adventitia after vascular injury. However, the physiological role of Angiotensin II (Ang II) in the adventitia has not been studied at a cellular level. This study was designed to assess the role of Ang II in the growth response of cultured adventitial fibroblasts (AFs). Adventitial explants of the rat thoracic aorta showed outgrowth of AFs within 5-7 days. Ang II caused hyperplastic response of AF cultures. The Ang II-induced mitogenic response of AFs was mediated primarily by the AT1 receptor. Ang II caused a rapid induction of immediate early genes (c-fos, c-myc and jun B). Induction of c-fos expression was fully blocked by an AT1 receptor antagonist but not by an AT2 receptor antagonist. Epidermal growth factor (EGF), platelet-derived growth factor-BB (PDGF-BB) and basic fibroblast growth factor (bFGF) induced DNA synthesis in AFs. Co-stimulation of AFs with the growth factors and Ang II potentiated the incorporation of 3H-thymidine into DNA. Results from this study indicate that Ang II causes mitogenesis of AFs via AT1 receptor stimulation and potentiates the responses to other mitogens. These data suggest that the Ang II may play an important role in regulating AF function during vascular remodeling following arterial injury.
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PMID:Angiotensin II stimulates proliferation of adventitial fibroblasts cultured from rat aortic explants. 1057 43

We recently reported that the activation of nuclear factor-kappaB (NF-kappaB) promotes inflammation in rats harboring both human renin and angiotensinogen genes (double-transgenic rats [dTGR]). We tested the hypothesis that the antioxidant pyrrolidine dithiocarbamate (PDTC) inhibits NF-kappaB and ameliorates renal and cardiac end-organ damage. dTGR feature hypertension, severe renal and cardiac damage, and a 40% mortality rate at 7 weeks. Electrophoretic mobility shift assay showed increased NF-kappaB DNA binding activity in hearts and kidneys of dTGR. Chronic PDTC (200 mg/kg SC) treatment decreased blood pressure (162+/-8 versus 190+/-7 mm Hg; P=0.02) in dTGR compared with dTGR controls. The cardiac hypertrophy index was also significantly reduced (4.90+/-0.1 versus 5.77+/-0.1 mg/g; P<0. 001). PDTC reduced 24-hour albuminuria by >95% (2.5+/-0.8 versus 57. 1+/-8.7 mg/d; P<0.001) and prevented death. Vascular injury was ameliorated in small renal and cardiac vessels. Electrophoretic mobility shift assay showed that PDTC inhibited NF-kappaB binding activity in heart and kidney, whereas AP-1 activity in the kidney was not decreased. dTGR exhibited increased left ventricular c-fos and c-jun mRNA expression. PDTC treatment reduced c-fos but not c-jun mRNA. Immunohistochemistry showed increased p65 NF-kappaB subunit expression in the endothelium and smooth muscle cells of damaged small vessels, as well as infiltrating cells in glomeruli, tubules, and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. PDTC also prevented the NF-kappaB-dependent transactivation of the intercellular adhesion molecule ICAM-1 and inducible nitric oxide synthase. Monocyte infiltration was markedly increased in dTGR kidneys and hearts. Chronic treatment reduced monocyte/macrophage infiltration by 72% and 64%, respectively. Thus, these results demonstrate that PDTC inhibits NF-kappaB activity, ameliorates inflammation, and protects against angiotensin II-induced end-organ damage.
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PMID:NF-kappaB inhibition ameliorates angiotensin II-induced inflammatory damage in rats. 1064 97

Cardiac hypertrophy is an adaptive process to an increased hemodynamic overload. When cardiomyocytes cultured on silicone dishes were stretched, second messengers such as protein kinase C (PKC), Raf-1 kinase, and mitogen-activated protein (MAP) kinases were activated, which were followed by increased protein synthesis. Moreover, pretreatment with an angiotensin II (AngII) type 1 receptor antagonist dimished an increase in protein synthesis, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. These suggest the linkage of the cardiac renin-angiotensin system to the formation of pressure-overload hypertrophy. Indeed, in the stretch-conditioned medium the levels of AngII concentration were increased. Also, mechanical stretch enhanced endothelin (ET)-1 release from the cardiomyocytes and activated the Na(+)/H(+) exchanger independently of these vasoactive peptides. In the second part, we examined AngII-induced signaling pathways both in cardiac myocytes and in cardiac fibroblasts. AngII-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts AngII activated MAP kinases through a pathway including the Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and PKC activation was necessary in cardiac myocytes. We further explored norepinephrine (NE)-induced signaling pathways in cardiac myocytes. NE activated Raf-1 kinase and MAP kinases and increased amino acid uptake in cardiomyocytes of neonatal rats. beta-adrenoceptor (AR) stimulation as well and alpha1-AR stimulation was involved in NE-induced MAP kinase activation. It is noteworthy that unlike in other cell types not only PKC activation but also protein kinase A (PKA) activation increased the activities of Raf-1 kinase and MAP kinases in cardiac myocytes and induced cell growth. Finally, we observed that beta-AR-induced activation of MAP kinases is dependent on both Gs/cAMP/PKA and Gi/Src/Ras signaling pathways and that phosphorylation of beta-AR is critical to the cross talk between these signaling pathways.
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PMID:Molecular basis of cardiac hypertrophy. 1066 10

Three experiments were performed to determine whether renal afferent pathways were activated by the diuretic drug, furosemide. It was hypothesized that activated neurons of the renal afferent pathway would express the protein product Fos of the c-fos immediate early gene and be identified by immunocytochemical staining for Fos in the cell nucleus. In the first two experiments, rats were injected with either furosemide (5 mg) or vehicle solution (sterile isotonic saline) and sacrificed either 1.75 h (short-survival experiment) or 3.5 h (long-survival experiment) after injection. In both experiments, the furosemide-treated rats had significantly more Fos-positive cell nuclei than vehicle-treated rats in the subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT), supraoptic nuclei (SON), and magnocellular region of the paraventricular nuclei (PVN) - areas previously shown to be activated by hypovolemia or peripheral angiotensin. In the short-survival experiment, the furosemide-treated rats had more Fos-positive cell nuclei in the nucleus of the solitary tract (NTS) and in the dorsal horn of the spinal cord at spinal levels T(11), T(12), and T(13). In contrast, furosemide treatment did not produce more Fos-positive cell nuclei in the NTS and dorsal horn of the spinal cord in the long-survival experiment. These results suggest that the activation of the SFO, OVLT, SON and PVN may be via a different mechanism than that of NTS or spinal cord dorsal horn. Based upon our previous work, we hypothesized that the NTS and spinal cord dorsal horn labeling was due to activation of sympathetic afferents originating in the kidney and labeling in forebrain structures was due to stimulation by angiotensin generated by renal renin release. To test this hypothesis, a third experiment was devised that was identical to the short-survival experiment, except that all rats had bilateral renal denervation surgery 1 week previously. In this experiment, furosemide administration increased the number of Fos-positive cells in the SFO, OVLT, SON and PVN, but not in the caudal thoracic spinal cord or NTS. These results together with the results of first two experiments lend support to our hypothesis that furosemide-induced neuronal activation in the thoracic spinal cord and NTS is due to activation of second- and/or third-order neurons of a renal sympathetic afferent pathway. Furosemide-induced activation in the SFO, OVLT, SON and PVN does not depend on renal innervation. It is hypothesized that activation in these forebrain regions depends on the action of angiotensin II that is generated after furosemide treatment. Our results indicate that both a hormonal pathway and a renal sympathetic afferent pathway conduct information from the kidney to the central nervous system (CNS) after furosemide treatment.
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PMID:Activation of renal afferent pathways following furosemide treatment. I. Effects Of survival time and renal denervation. 1076 Apr 98

The goal here and in the accompanying paper was to evaluate the two pathways used by the kidney to provide information to the central nervous system (CNS); e.g., the indirect, hormonal route via activation of the renin-angiotensin system and the direct pathway via activation of sympathetic afferents in the caudal thoracic spinal cord. Here, three experiments were designed to evaluate the actions of angiotensin elicited by subcutaneous injection of furosemide on neural activation of the CNS. The number of neurons immunocytochemically staining for the protein product (Fos) of the c-fos gene was used as an index of neuronal activation. In the first experiment, furosemide injection was preceded by treatment with a dose of Captopril, CAP, (an angiotensin-converting enzyme (ACE) inhibitor) that blocks the peripheral but not the central formation of angiotensin II. In the second experiment, furosemide injection was preceded by treatment with a higher dose of CAP; this dosage blocks the peripheral and central formation of angiotensin II. In the third experiment, furosemide injection was preceded by treatment with Losartan, a competitive receptor antagonist of type I angiotensin II receptors at a dose that would block central and peripheral angiotensin receptors. Control animals in each experiment received injections of vehicle (sterile isotonic saline) instead of furosemide. In each experiment, rats were sacrificed 1.75 h following furosemide or saline injection by transcardial perfusion and tissues were immunocytochemically processed for demonstration of Fos antigen. Rats receiving furosemide plus the low CAP dose showed more Fos-positive cells than control rats in the subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT), supraoptic nucleus (SON), magnocellular region of the paraventricular nucleus, nucleus of the solitary tract (NTS), and caudal thoracic/rostral lumbar spinal cord dorsal horn. Rats receiving furosemide plus Losartan or furosemide plus the higher CAP dose did not show increased Fos immunoreactivity in any of the abovementioned structures relative to their respective control animals. We conclude that the receptor-mediated action of angiotensin II is in some way involved in the activation of the pathway that occurs in the SFO, OVLT, SON, and magnocellular region of the paraventricular nucleus (PVN) in response to furosemide treatment. It is possible that the furosemide-induced activation in the SON and PVN is not due to direct actions of angiotensin II on angiotensin receptors in those structures, but instead occurs synaptically as a result of inputs from the SFO and OVLT, which have themselves been activated directly by angiotensin II. In the accompanying paper, furosemide-induced activation in the NTS and caudal thoracic spinal cord is abolished by prior bilateral renal denervation, meaning that these neurons are likely part of a renal afferent pathway. Here, these structures did not elaborate Fos in animals injected with furosemide plus the high CAP dose or furosemide plus Losartan. Thus, the present results also suggest that the central blockade of the formation of angiotensin II or blockade of the actions of angiotensin II prevents in some way the activation of the renal afferent pathway mediated by the renal nerves (the direct pathway) in response to the actions of furosemide. Therefore, these results suggest that central angiotensin II is somehow involved in "priming" or increasing the sensitivity of the direct renal afferent pathway. Taken together with the accompanying paper, our results indicate that interruption of the direct pathway via renal denervation did not interfere with the elaboration of Fos in the lamina terminalis; in contrast, modification of the humoral renal afferent pathway can affect the sensitivity of the direct pathway. These results may have important implications for pathophysiological changes associated with fluid balance disorders including renal hypertension.
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PMID:Activation of renal afferent pathways following furosemide treatment. II. Effect Of angiotensin blockade. 1076 Apr 99

Tissue factor (TF), a main initiator of clotting, is up-regulated in vasculopathy. We tested the hypothesis that chronic in vivo angiotensin (ANG) II receptor AT(1) receptor blockade inhibits TF expression in a model of ANG II-induced cardiac vasculopathy. Furthermore, we explored the mechanisms by examining transcription factor activation and analyzing the TF promoter. Untreated transgenic rats overexpressing the human renin and angiotensinogen genes (dTGR) feature hypertension and severe left ventricular hypertrophy with focal areas of necrosis, and die at age 7 weeks. Plasma and cardiac ANG II was three- to fivefold increased compared to Sprague-Dawley rats. Chronic treatment with valsartan normalized blood pressure and coronary resistance completely, and ameliorated cardiac hypertrophy (P < 0.001). Valsartan prevented monocyte/macrophage infiltration, nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activation, and c-fos expression in dTGR hearts. NF-kappaB subunit p65 and TF expression was increased in the endothelium and media of cardiac vessels and markedly reduced by valsartan treatment. To analyze the mechanism of TF transcription, we then transfected human coronary artery smooth muscle cells and Chinese hamster ovary cells overexpressing the AT(1) receptor with plasmids containing the human TF promoter and the luciferase reporter gene. ANG II induced the full-length TF promoter in both transfected cell lines. TF transcription was abolished by AT(1) receptor blockade. Deletion of both AP-1 and NF-kappaB sites reduced ANG II-induced TF gene transcription completely, whereas the deletion of AP-1 sites reduced transcription. Thus, the present study clearly shows an aberrant TF expression in the endothelium and media in rats with ANG II-induced vasculopathy. The beneficial effects of AT(1) receptor blockade in this model are mediated via the inhibition of NF-kappaB and AP-1 activation, thereby preventing TF expression, cardiac vasculopathy, and microinfarctions.
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PMID:Angiotensin II (AT(1)) receptor blockade reduces vascular tissue factor in angiotensin II-induced cardiac vasculopathy. 1088 Mar 68

The 5-HT(2A/2C) agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) stimulates hypothalamic neurons to increase the secretion of several hormones. This study addressed two questions: 1) are the neuroendocrine effects of DOI mediated via activation of 5-HT(2A) receptors; and 2) which neurons are activated by 5-HT(2A) receptors. The 5-HT(2A) antagonist (+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL 100,907; 0.001, 0.01, or 0.1 mg/kg, s.c.) was administered before rats were challenged with DOI (2.5 mg/kg, i.p.). MDL 100,907 produced a dose-dependent inhibition (ED(50) congruent with 0.001 mg/kg) of the effect of DOI on plasma levels of ACTH, corticosterone, oxytocin, prolactin, and renin without altering basal hormone levels. Complete blockade of the effect of DOI was achieved for all hormones at MDL 100,907 doses of 0.01-0.1 mg/kg. In a parallel experiment, DOI was injected 2 hr before killing to determine its effects on the expression of Fos, the product of the immediate early gene c-fos. DOI induced an increase in Fos immunoreactivity in corticotropin-releasing factor (CRF) and in oxytocin-expressing neurons but not in vasopressin-containing neurons in the hypothalamic paraventricular nucleus or CRF cells in the amygdala. Pretreatment with MDL 100,907 (0.1 mg/kg, s.c.) blocked the DOI-induced increase in Fos expression in all regions including the hypothalamus, amygdala (central and corticomedial), bed nucleus of the stria terminalis, and prefrontal cortical regions. The combined neuroanatomical and pharmacological observations suggest that the neuroendocrine responses to DOI are mediated by activation of neurons in the hypothalamic paraventricular nucleus and associated circuitry. Furthermore, selective activation of 5-HT(2A) receptors mediates the hormonal and Fos-inducing effects of DOI.
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PMID:5-HT2A receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells. 1133 86

In transgenic hypertensive TGR(mREN2)27 rats (TGR) harboring the murine Ren-2 gene an inverse 24h blood pressure (BP) profile was described in relation to a normal pattern in heart rate (HR) and motility (MA), normotensive Sprague-Dawley rats (SDR) were used as controls. Transgenic rats as an animal model of human secondary hypertension (non-dipper) was studied in detail at different levels: (1) Radiotelemetry was applied to document gross circadian rhythms/rhythm disturbances in cardiovascular functions, MA and body temperature under normal LD conditions, under DD and after a light pulse. (2) Signal transduction of the overexpressed renin-angiotensin in TGR was studied by determation of AT1-receptors in kidney glomeruli together with kidney functions. (3) Expression of key processes involved in increased sympathetic regulation in TGR, mRNAs, the tyrosine-hydroxylase (TH) and norepinephrine (NE) reuptake1-carrier were determined. (4) In the SCN mRNA of c-fos and c-jun were determined under LD and after light pulse. (5) In primary cultures of pinealocytes the effects of adrenergic agonists and antagonists were evaluated on second messenger (cAMP, cGMP) accumulation and melatonin release. The results of these studies clearly demonstrate that the additional mouse renin genin in TGR greatly affected not only the renin-angiotensin-system and led--as expected--to an increased BP in this rat but also disturbed circadian rhythms from the BP pattern down to the level of hormones, processes of signal transduction, and expression of transcription factors and clock genes. In conclusion, the expression of a single additional gene is able to disturb the circadian system of an animal in a highly complex way. These findings are importance for chronobiologic as well as pharmacologic research.
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PMID:Transgenic TGR(mREN2)27 rats as a model for disturbed circadian organization at the level of the brain, the heart, and the kidneys. 1291 22

Central renin-angiotensin system (RAS) is as important as the peripheral RAS in the control of the cardiovascular homeostasis in the adult. However, previous fetal studies on angiotensin II (ANG II)-induced cardiovascular responses focused exclusively on the peripheral side. Thus, few data exist characterizing the in utero development of central angiotensin-mediated pressor responses. The present study determined cardiovascular responses to central application of ANG II in the chronically prepared near-term ovine fetus, and determined the action sites marked by c-fos expression in the fetal hypothalamus following intracerebroventricular (icv) injection of ANG II in utero. ANG II significantly increased fetal systolic, diastolic, and mean arterial pressure (MAP) within 5 min after injection of this peptide into the brain. Adjusted fetal MAP against amniotic pressure was also increased by icv ANG II, associated with increased c-fos in the central putative cardiovascular area--the paraventricular nuclei (PVN). Application of ANG II also induced intense c-fos expression in the supraoptic nuclei (SON), accompanied by a significant increase of fetal plasma vasopressin (AVP) levels, while maternal blood pressure (BP) and plasma AVP concentration were not changed. These results indicate that the central ANG II-mediated pressor response is functional at the last third of gestation, acting at the sites consistent with the cardiovascular neural network in the hypothalamus.
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PMID:In utero development of central ANG-stimulated pressor response and hypothalamic fos expression. 1460 57


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